Ever since HIV was identified as the etiological cause of AIDS a decade ago, chemotherapy of AIDS has been a very challenging scientific endeavor. Antiviral nucleoside agents such as AZT, ddC, ddl, d.sub.4 T and 3TC being Reverse Transcriptase (R.T.) inhibitors are approved for clinical use. Although these nucleoside based drugs can extend the life of the patient, they are associated with several side effects and are not capable of curing the disease.
The urge for the promising RT inhibitors to cure AIDS, resulted in the identification of a group of coumarin derivatives isolated (Ref: M R Boyd et al, J. Med. Chem., 1992, 35, 2735-2743) from genus Calophyllum as HIV-1 specific non-nucleoside inhibitors, among which Calanolide A represented by formula II (X=O) is the most potent and is currently undergoing clinical trials (phase III). The structural formula of the above compound is shown herebelow: ##STR2##
Calanolides, a `dipyrano-coumarin` class of compounds are active not only against the AZT-resistant strain of HIV-1, but also against virus strains resistant to some other non-nucleoside inhibitors such as TIBO pyridinone, and neviropine. The main drawbacks of this class of compounds are (a) poor solubility of this class of compounds in the physiological medium and (b) lesser stability of the coumarin ring system in biological environment.
It, thus, would be desirable to prepare the New Chemical Entities (NCEs) having calanolide skeleton but with better therapeutic index. In addition, the NCEs are desirable to overcome the problems associated with calanolides such as stability and solubility in the physiological medium as noted above.
Quinolinones are shown to be part structures of several bio-active compounds with profound bio-efficacy. Unlike the lactone bond in coumarins, the lactam bond in quinolinones is highly stable.
This invention, thus deals with the synthesis of novel `dipyrano-quinolinone` class of compounds related to calanolide structural frame work as NCEs and envisaged to circumvent the problems associated with calanolides and have improved therapeutic indices.
The invention deals with the synthesis of novel and new `dipyrano-quinolinone` class of compounds that is presented in the form of patent, where the major differences in the structural arrangement is the replacement of coumarin ring oxygen (at position 1) of calanolide structure of formula II (X=O) with nitrogen (at position 1) in the new `quinolinone` ring system represented by formula II (X=NH). These quinolinone analogues of calanolides are NCEs and are envisaged as potential candidate molecules as anti-HIV agents. The above replacement is not obvious and needs human effort and ingenuity to achieve it. The synthesis and biological activity of `dipyrano-quinolinone` derivatives is reported for the first time in this patent. The rationale for the synthesis of these `dipyrano-quinolinones` reported in this specification are as follows:
1. Replacement of oxygen (at position 1) of natural products, calanolides, with nitrogen leads to dipyrano-quinolinones as anti-HIV agents with better therapeutic index. PA1 2. The inherent problems associated with naturally occurring calanolides such as metabolic stability and solubility in physiological medium can be circumvented with the new dipyrano-quinolinone derivatives that are reported in this patent. PA1 3. The derivatisation of water-soluble derivatives of these new chemical entities represented in this patent are easily possible. PA1 4. The metabolic stability is expected to enhance due to the presence of nitrogen atom in the skeleton of dipyrano-quinolinones derivative presented in this patent. PA1 5. The structure activity relationship coupled with positive activity against calanolide resistant strain of HIV virus can be explored due to the presence of nitrogen atom in the dipyrano-quinolinone system. PA1 a) reacting substituted aniline with an acid chloride or 1,3-dioxinone to provide the amides, PA1 b) cyclisation of amides in the presence of acids to provide quinolinones, PA1 c) reacting quinolinone with tigloyl chloride to provide the acylation products, PA1 d) cyclisation of the acylation products in the presence of acid or base to provide the chromanone ring, PA1 e) reacting the chromanone with substituted propargyl chloride to provide chromene, PA1 f) reacting the chromanone with suitable reducing agent to provide the new chemical entities the `dipyrano-quinolinone` class of compounds, if desired, PA1 g) hydrogenation of the chromene ring to give the dihydro derivatives, and PA1 h) reduction of the dihydro derivatives with reducing agents to get the dihydro analogues.